This invention is concerned with compounds of the formula 
where
X is oxygen, sulfur, xe2x80x94NH, xe2x80x94NR1, xe2x80x94Nxe2x80x94CN, xe2x80x94Nxe2x80x94OR1 or xe2x80x94Nxe2x80x94NO2:
Y is a single bond, xe2x80x94Cxe2x95x90Cxe2x80x94, or xe2x80x94NH;
R1 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclo, (aryl)alkyl, (cycloalkyl)alkyl, (substituted amino)alkyl, or (heterocyclo)alkyl; and
R2 is aryl or heterocyclo.
The compounds of formula I are useful in the treatment of arrhythmia. The invention is also concerned with pharmaceutical compositions comprising one or more of the novel compounds as an active antiarrhythmic agent either alone or in combination with other cardiovascular agents such as a xcex2-blocker or other antiarrhythmic agent; and a method of treating arrhythmia by administration of one of the novel compounds or compositions thereof to a patient in need of such treatment.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to both straight and branched chain groups having 1 to 8 carbon atoms, preferably 1 to 5 carbons, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the various branched chain isomers thereof, such as isopropyl, t-butyl, isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl and the like; as well as such groups substituted by, one or more substituents such as halo, alkoxy, amino, substituted amino, aryl, cycloalkyl, hydroxy, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, alkylthio and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94.
The term xe2x80x9calkylthioxe2x80x9d refers alkyl-Sxe2x80x94.
The term xe2x80x9calkenylxe2x80x9d refers to any of the above alkyl groups further containing at least one carbon to carbon double bond.
The term xe2x80x9calkynylxe2x80x9d refers to any of the above alkyl groups further containing at least one carbon to carbon triple bond.
The term xe2x80x9calkanoylxe2x80x9d refers to alkyl-C(O)xe2x80x94.
The term xe2x80x9ccycloalkylxe2x80x9d refers to saturated cyclic hydrocarbon groups containing 3 to 8 ring carbons optionally substitued with one or more substituents such as alkyl or hydroxy.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, iodine and fluorine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, 1-naphthyl, 2-naphthyl, phenanthrene or dihydrophenanthrene; or such groups substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkylthio, alkoxy, halo, nitro, cyano, hydroxy, amino, substituted amino, phenyl, xe2x80x94C(O)-phenyl, substituted phenyl, xe2x80x94C(O)-substituted amino, heterocycle, carboxylic acid or carboxylic ester.
The term xe2x80x9carylxe2x80x9d also includes those groups listed above fused to a five- or six-membered ring which optionally contains an oxygen, sulfur or nitrogen atom. The five- or six-membered ring may further optionally be substituted with for example, alkyl or xe2x80x94phenylxe2x80x94CF3.
The term xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheteroxe2x80x9d refers to fully saturated or unsaturated rings of five or six atoms containing one or two oxygen and/or sulfur atoms and/or one to four nitrogen atoms provided that the total number of hetero atoms in the ring is four or less. Exemplary monocyclic heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl and imidazolyl.
The term heterocyclo or hetero also includes bicyclic rings wherein the five- or six-membered ring containing oxygen and/or sulfur and/or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available atom.
Exemplary bicyclic hetero groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl and 4-, 5-, 6- or 7-benzofuranyl.
The term heterocyclo or hetero also includes such monocyclic and bicyclic rings wherein an available atom is substituted by one or more substituents such as alkyl, aryl, alkylthio, alkoxy, halo, nitro, keto, cyano, hydroxy, azo, oxo, thiazo, amino, substituted amino, carboxylic acid, carboxylic ester, or alkoxy further substituted with a carboxylic acid or a five- to eight-membered ring optionally containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted by groups such as alkyl or halogen.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to a group of the formula xe2x80x94NZ2Z3 wherein Z2 is hydrogen, alkyl, cycloalkyl, aryl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl and Z3 is hydrogen, alkyl, cycloalkyl or aryl further substituted with a carboxylic acid or carboxylic ester, provided that when Z2 is hydrogen, then Z3 is other than hydrogen; or Z2 and Z3 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl; or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, aryl or hydroxy.
Throughout the specification, groups and substituents thereof are chosen to provide stable moieties and compounds.
The compounds of formula I may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compound I with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those having ordinary skill in the art.
The compounds of formula I may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compound I in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
A compound of the formula I may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);
b) Methods in Enzymology, Vol. 42, 309-396, edited by K. Widder et al. (Academic Press, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, 113-191 (1991);
d) Advanced Drug Delivery Reviews, H. Bundgaard, 8, 1-38 (1992);
e) Journal of Pharmaceutical Sciences, H. Bundgaard et al., 77, 285 (1988); and
f) Chem Pharm Bull, N. Kakeya et al., 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in diastereomeric forms or in mixtures thereof. The below described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographyc or fractional crystallization.
The compounds of formula 1 are useful in the treatment of arrhythmia. More specifically, the compounds of the present invention have the pharmacological properties required for the antiarrhythmic agents of Class III.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter 1Na and 1Ca respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK)K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (1to) and inward rectifier (1K1)K+ current are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that 1K consists of two pharmacologically and kinetically distinct K+ current subtypes, 1Kr (rapidly activating and deactivating) and 1Ks (slowly activating and deactivating).
Most Class III agents that are known to be in development predominantly block 1Kr. These agents have a potential liability in that they have an enhanced risk of proarrhythmia at slow heart rates. The compounds of the present invention prolong the mycocardial action potential in vitro without a significant depression of the Vmax and with the prolongation of interval in anesthetized dogs. In addition the compounds of the present invention selectively block IKs. The preferred compounds of the present invention are those which have selectivity of IKs:IKr greater than or equal to 5.
The compounds of the present invention are effective in treating and preventing all types of arrhythmias including ventricular and atrial (supraventricular) arrhythmias. The compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fibrillation.
In the novel method of this invention of treating arrhythmia, a novel compound or pharmaceutically acceptable salt thereof, is administered in an amount ranging from about 0.0001 to about 20 mg per kg of body weight per day, preferably from about 0.001 to about 10 mg per kg of body weight per day in a single dose or in 2 to 4 divided doses.
The novel compounds of this invention can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.
The compounds, or pharmaceutically acceptable salts thereof, of the present invention, in the described dosages, are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, or the like prepared by art recognized procedures. The amount of active compound in such therapeutically useful compositions or reparations is such that a suitable dosage will be obtained.
The preferred compounds of the present invention are those ompounds of formula I where:
X is oxygen or Nxe2x80x94CN;
Y is a single bond or xe2x80x94Cxe2x95x90Cxe2x80x94; and
R1 is alkyl, cycloalkyl, (aryl)alkyl, (cycloalkyl)alkyl, or (substituted amino)alkyl.
The compounds of the instant invention may be obtained by methods exemplified by the following descriptions.
The compounds of formula 1 wherein X is O and Y is a single bond or xe2x80x94Cxe2x95x90Cxe2x80x94 (compounds of formula 1a), can be prepared as outlined in Scheme 1 below. 
The acid chloride (Zxe2x95x90Cl) of formula 2 is reacted with an amine of formula 3 in the presence of a base such as triethylamine and an organic solvent such as dichloromethane, tetrahydrofuran or dimethylformamide etc. to form the compounds of formula 1a. 
Alternatively, compounds of formula 1a can be prepared from an acid of formula 2 (Zxe2x95x90OH) and an amine of formula 3 in an organic solvent in the presence of a carbodiimide such as dicyclohexylcabodiimide or 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (WSC).
Compounds of formula 1 wherein X is S, can be prepared from compounds of formula 1 wherein X is O by treatment with a thionating agent such as phosphorus pentasulfide (P4S10) or the Lawesson""s reagent.
Compounds of formula 2 and 3 are commercially available or they can be prepared by methods described in the literature.
The compounds of formula I wherein X is NCN and Y is a single bond or xe2x80x94Cxe2x95x90Cxe2x80x94 (i.e., compounds of formula Ib), can be prepared as outlined in Scheme 2. 
The nitrile of formula 4 is converted to the imino ether of formula 5 by treatment with hydrochloric acid in ethanol. The imino ether 5 is then reacted with cyanamide to provide a compound of formula 6 which on reaction with an amine of formula 3 provides the compounds of formula 1b. Compounds of formula 4 are commercially available or they can be prepared by methods described in the literature.
The compounds of formula 1 wherein X is NCN and Y is NH (i.e., compounds of formula 1c), can be prepared as outlined in Scheme 3. 
The amine of formula 7 is converted to the phenyl ester of formula 8 by treatment with diphenylcyanocarbonimidate in the presence of a base (e.g., sodium hydride, diisopropylethyl amine). The compound of formula 8 is converted to the compounds of formula 1c by treatment with an amine of formula 3 in an organic solvent. Compounds of formula 7 are commercially available or they can be prepared by methods described in the literature.
Alternatively, compounds of formula 1 wherein X is NCN and Y is NH, can be prepared by methods similar to those described in the literature such as that by Atwal et. al. Tetrahedron Letters, Vol. 30, pp 7313-7316 (1989) and references therein.
The compounds of formula 1 wherein X is O or S and Y is NH (i.e., compounds of formula 1d), can be prepared as outlined in Scheme 4. 
The amine of formula 7 is reacted with an isocyanate or isothiocyanate of formula 9 in an organic solvent to provide the compounds of formula 1d. 
Alternatively, the compounds of formula 1 wherein X is O or S and Y is NH, can be prepared by sequential treatment of an amine of formula 7 with an arylchloroformate (e.g., phenylchloroformate) and an amine of formula 3.
Compounds of formula 1 wherein X is S, can be prepared from compounds of formula 1 wherein X is O by treatment with a standard thionating agent such as phosphorus pentasulfide (P4S10) or the Lawesson""s reagent. Compounds of formula 9 are commercially available or they can be prepared by conventional methods described in the literature.
The compounds of formula 1 wherein R2 contains an aryl or a heterocyclo substituent (formula 1e) may be prepared according to Scheme 5. 
Compounds of formula 1e can be prepared from compounds of formula 8 wherein W is a suitable leaving group such as halogen or triflate by treatment with a heterocyclo group or an aryl ring containing a suitable reacting group such as an amino group, boronic acid and trialkyltin in the presence of a suitable catalyst (base, palladium etc.). Compounds of formula 8 are prepared by methods described in Schemes 1 to 4.
The compounds of formula 1 wherein R2 contains a heterocyclic substituent (oxazole, imidazole, oxadiazole, thiadiazole etc.), can also be prepared from compounds of formula 1* wherein R2 contains a suitable heterocyclo forming group such as an acid or a derivative thereof as described in Scheme 6. 
Compounds of formula 1f are prepared by treatment with a suitable heterocyclo forming reagent (amidine, hydroxyamidine etc.). This transformation can also be accomplished in a stepwise fashion by modification of methods described in the literature.
All other compounds of formula I may be prepared by modification of the procedures discussed herein as known by those having ordinary skill in the art. The intermediates used to prepare compounds of formula I are described herein or may be derived from known compounds by those having ordinary skill in the art or are commercially available.